Structural basis for the function and inhibition of an influenza virus proton channel

Article

关键词: M-2 ION-CHANNEL;    A VIRUS;    ADAMANTANE RESISTANCE;    TRANSMEMBRANE DOMAIN;    MEMBRANE-PROTEINS;    M2;    MECHANISM;    MODEL;    HELIX;    STATE;   

DOI  :  10.1038/nature06528

来源: SCIE

【 摘 要 】

The M2 protein from influenza A virus is a pH- activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti- influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% ( ref. 1). Here we describe the crystal structure of the transmembrane- spanning region of the homotetrameric protein in the presence and absence of the channel- blocking drug amantadine. pH- dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating(2). The drug- binding site is lined by residues that are mutated in amantadine- resistant viruses(3,4). Binding of amantadine physically occludes the pore, and might also perturb the pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2- channel blockers.

【 授权许可】

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